N-trityl-imidazoles for treating fungal infections

ABSTRACT

WHEREIN THE SUBSTITUENTS ARE AS ABOVE DEFINED AND HAL IS HALOGEN. THESE COMPOUNDS ARE USEFUL AS ANTIMYCOTICS.   1-(((X)A-PHENYL)-C(-PHENYLENE-(X&#34;)A&#34;)-),(X&#39;&#39;)A&#39;&#39;-BENZENE   WITH A TRITYL HALIDE OF THE FORMULS:   2-R,4-R1,5-R2-IMIDAZOLE   WHEREIN R, R1 AND R2 ARE HYDROGEN, LOWER ALKYL OR PHENYL, OR R1 AND R2 TOGETHER FORM AN ANELLATED BENZENE RING, X, X&#39;&#39; AND X&#34; ARE ALKYL OF 1 TO 12 CARBON ATOMS OR AN ELECTRO-NEGATIVE MOIETY, AND N, N&#39;&#39; AND N&#34; ARE AN INTEGER FROM 0 TO 2, OR PHARMACEUTICALLY ACCEPTABLE ACID SALTS THEREOF MAY BE PRODUCED BY REACTING A SILVER SALT OR ALKALI METAL SALT OF AN IMIDAZOLE OF THE FORMULA:   ,2-R,4-R1,5-R2-IMIDAZOLE   1-(((X)A-PHENYL)-C(-PHENYLENE-(X&#34;)A&#34;)(-PHENYLENE-(X&#39;&#39;)A&#39;&#39;)-)   N-TRITYL-IMIDAZOLES AND SALTS THEREOF OF THE FORMULA:

Ce Patented 1 3,660,576 R N N-TRlTYL-IMIDAZOLES FOR TREATING R I R FUNGAL INFECTIONS x N Karl H. Buchel, Leverkusen, and Manfred Plempel, 5

Wuppertal-Elherfeld, Germany, assignors to Farhen- 2 fabriken Bayer Aktiengesellschaft, Leverkusen, Germany No Drawing. Original application Sept. 9, 1968, Ser. No. 758,594. Divided and this application May 11, 1970, Ser. No. 36,396 Claims priority, application Germany, Sept. 15, 1967, X (I) F 53,504 wherein R, R and R are hydrogen, lower alkyl or phen- A611 27/00 yl, or R and R together form an anellated benzene ring, CL 424z73 1o Clam X, X and X" are alkyl of 1 to 12 carbon atoms or an 15 electro-negative moiety, and

n, n and n" are an integer from 0 to 2, or pharma- ABSTRACT OF THE DISCLOSURE ceutically acceptable acid salts thereof. When R, R or N-trityl-imidazoles and salts thereof of the formula: R are alkyl moieties, those having 1 to 4 carbon atoms are preferred. When X, X or X" is an alkyl moiety, it is B N preferred that such have 1 to 12 carbon atoms and such I moieties having 1 to 4 carbon atoms are especially prexn R N R fe'rred. Electro-negative substituents which are particular- I 1 x ly'preferred are the halogens, i.e., fluorine, chlorine, bro- Q- Q mine and iodine, N0 CF CN, as well as S-lower alkyl and O-lower alkyl; it is preferred that the alkyl moieties have 1 to 4 carbon atoms. The term alkyl and lower alky comprises straight chain as well as branched chain alkyl moieties and also include those containing a double x",,- bond.

The salts of the N-trityl-imidazoles (I) are the pharwherein R, R and R are hydrogen, lower alkyl or phenmaceutically acceptable non-toxic acid salts. Examples of yl, or R and R together form an anellated benzene suitable acids are the hydrohalic acids (hydrochloric being ring, particularly preferred), phosphoric acid, monoand bi- X, X and X" are alkyl of l to 12 carbon atoms or an functional carboxylic acids, such as acetic acid, propionic electro-negative moiety, and acid, maleic acid, succinic acid, fumaric acid, tartaric n, n and n" are an integer from 0 to 2, or pharmaceuacid, citric acid, salicylic acid, sorbic acid, lactic acid and tically acceptable acid salts thereof may be produced 1,5-naphthalene-disulphonic acid. The hydrohalides, espeby reacting a silver salt or alkali metal salt of an cially the hydrochlorides, lactates and salicylates are of imidazole of the formula: particular value.

I In a particularly preferred embodiment of the present R N invention, the N-trityl-imidazoles have the formula: R2 J73, N

with a trityl halide of the formula: 2 13 x,-

xu or x"..- N wherein the substituents are as above defined and Hal is halogen. These compounds are useful as antimycotics. N

QMQ This is a divisional of our copending application Ser. I No. 758,594 filed Sept. 9, 1968.

The present invention is concerned with N-trityl-imid azoles and salts thereof and the production of such com- (Ha) pounds. More particularly, the present invention is concerned with N-trityl-imidazoles and salts thereof of the wherein X, X and X" are alkyl of l to 12 carbon atoms formula: or electro-negative substituents and n, n and n" are 1 or X filal 'n' a l 1.. N

(III) wherein R, R and R X, X' and X and n, n and n" have the above meanings and Hal is chlorine, bromine or iodine, in an inert solvent such as benzene, toluene, hexane, cyclohexane or diethyl ether, at a temperature of from about 20 C. to about 110 C. [cf. Chem. Ber. 92, 92 (1959); 93, 570 (1960)].

The compounds of the present invention can also be prepared according to techniques per se known by reacting imidazole derivatives of the Formula III with tritylcarbinols (cf. the reaction of the carbinol corresponding to the halide IV with secondary amines). In this case, the imidazole is generally used in an excess of up to about 100%. If the process is carried out under pressure, molar amounts may be used. Furthermore, it may be expedient to carry out the elimination of water azeotropically in the presence of a high boiling inert organic solvent, su'bh as xylene, chlorobenzenes and the like, at the boiling pdi t'lt of the solvent used. In the absence of solvents, the proctfess is carried out at a temperature range of from about 140 C. to about 230 C. and preferably from about 170 C. to about 190 C. I

It may further be expedient to facilitate the elimination of water by working in the presence of dehydrating a'geh ts, such as e.g. alkaline earth metal oxides (MgO, BaO, bib) and of A1 0 approximately molar amounts being -geuerally used, but possibly also an excess of up to abol'lt -2-3 moles.

The following table gives the constants of some N-tritylimidazoles (I, II) by way of example:

M.P.: C.

(a) 1-(trisphenyl-methyl)-imidazole 226-227 (b) l-trisphenyl-methyl)-2-methyl-imidazole 225 (c) l-(trisphenyl-methyl) 2,4 dimethyl-imidazole 232 (d) l-(trisphenyl-methyl) 4,5 diphenyl-imidazole 228-230 (e) l-(p-chlorophenyl dipheriyl-methyD-imidazole 140 (f) l-(p-fluorophenyl diphenyl methyl)-imidazole 145 (g) 1-(p-tolyl-diphenyl-methyl)-imidazole 128 (h) l-(trisphenyl-methyl)-benzimidazole 180-181 (i) l-(o-chlorophenyl diphenyl-methyl)-imidazole 147-149 (j) l-(m chlorophenyl-diphenyl-methyl)-imidazole 114 (k) l-(p-bromophenyl diphenyl-methyl)-imidazole 152 (l) l-(o-fluorophenyl diphenyl methyl)-imidazole 185 (m) l-(m fluorophenyl diphenyl methyl)- imidazole v I r j 174 (n) l-(p-nitrophenyl diphenylmethyl)-imidazole 160-170 M.P.: C. (o) l (m trifluoromethylphenyl diphenylmethyl)-imidazole 156 (p) l-(p-cyanophenyl diphenyl-methyl)-imidazole 164 (q) l-(o-methoxyphenyl diphenyl methyl)- imidazole (r) l-(p-methylthiophenyl diphenyl methyl)- imidazole 142 (s) l-(p-fluorophenyl diphenyl methyl)-2- methyl-imidazole 199 (t) 1-(p-fluorophenyl-p-chlorophenyl phenylmethyl)-imidazole 144 (u) 1-(p-chlorophenyl-m-fluorophenyl phenylmethyl)-imidazole 116 (v) 1 (p chloro m nitrophenyl diphenylmethyl)-imidazole (w) 1-(p-bromophenyl-p-chlorophenyl phenylmethyl)-imidazole 140 (x) l-(m-cyanophenyl diphenyl-methyl)-imidazole 119 (y) l-(o-cyanophenyl diphenyl-methyl)-imidazole 149-151 heated, without a solvent, at about 180 C. for 5 hours. After cooling, the reaction product is reprecipitated from xylene in order to remove the'excess imidazole. After another reprecipitation from benzene light petrol, the pure 1- [p-chIorophenyl-diphenyl-methyl]imidazole is obtained. M.P. 140-143 0.; yield 53% of theory.

The same compound can also be obtained, when finely powdered silver salt of imidazole is suspended with the equimolar amount of p-ch10rophenyl-diphenyl-methyl chloride in absolute benzene, the mixture is heated with stirring and with the exclusion of light at boiling temperature for about 3 hours, the precipitated silver chloride is subsequently filtered off and the residue remaining after removal of the solvent is recrystallised from benzene/light petrol.

By analogous procedure, 1-(tris-phenyl-methyl)-imidazole is produced from 1-tris-phenyl-methyl-carbinol and imidazole and l-(p-tolyl-diphenyl)-imidazole is produced from l-p-tolyl-diphenyl-methyl-carbinol and imidazole.

The other compounds (I, II) can also be obtained according to the above processes. The conversion of the free compounds into the salts is likewise carried out in known manner.

Salts of trityl-imidazoles N-triphenyl-methyl-imidazolium lactate 31 g. N-trityl-imidazole are dissolved by heating in acetonitrile and 10 g. (0.11 mole), d,l-lactic acid are subsequently added. The residue remaining after distilling ofl? the solvent is caused to crystallise by covering it with ether, the crystallisation product is washed with ether and dried..

Yield 40 g. of a colourless crystalline powder of MR -180 C.

N-triphenyl-methyl-imidazolium chloride 31 g. N-trityl-imidazole are dissolved in 400 ml. carbon tetrachloride, and hydrogen chloride is subsequently passed into the solution at room temperature. The hydrochloride is precipitated after some time and filtered off with suction. Colourless crystals of MP. 155 C. after recrystallisation from acetone/ether 1:1. Yield 33 g.

The following salts are obtained in an analogous manner:

M.P.: C. N-triphenylmethyl-imidazolium maleate 106-117 N-triphenylmethyl-imidazolium tartrate 175-180 N-triphenylmethyl-imidazolium citrate 138-145 N-triphenylmethyl-imidazolium acetate 231 N-triphenylmethyl-imidazolium salicylate 145-168 N-triphenylrnethyl-imidazolium sorbate 148-160 N-triphenylmethyl-imidazolium succinate 188-189 N-triphenylmethyl-imidazolium fumarate 200-206 l-(p-chlorophenyl diphenyl methyl)-imidazolium-chloride 128-30 l-(p-chlorophenyl diphenyl methyl)-imidazolium-lactate 90 l-(p-chlorophenyl diphenyl methyl)-imidazolium-salicylate oil l-(m-chlorophenyl diphenyl methyl)-imidazo- Hum-hydrochloride 153 l-(o-chlorophenyl diphenyl methyD-imidazolium-chloride 1'59 l-(p-fluorophenyl diphenyl methyl)-imidazo lium-chloride 1 l-(p-fluorophenyl diphenyl methyl)-imidazolium-lactate 95 l-(o-fluorophenyl diphenyl methyl)-imidazolium-lactate 1 10 l-(m-fiuorophenyl diphenyl methyD-imidazolium-lactate 120 l-(p-fluorophenyl diphenyl methyl)-imidazo- Iium-salicylate 80 l-(p-cyanophenyl diphenyl methyl-)imidazov lium-chloride 147 1-(o-cyanophenyl diphenyl methyl)-imidazolium-chloride 13 1 l-(p-cyanophenyl diphenyl methyl)-imidazolium-lactate 90 The previously known antimycotics are effective either only against yeasts, such as e.g. Amphotericin B, or only against hyphomycetes, such as e.g. Griseofulvin.

In contrast thereto and surprisingly, the compounds (I, II) and their salts are effective against hyphomycetes as well as against yeasts, even in the case of oral administration. It is another advantage that the compounds according to the invention are well tolerated by warm-blooded animals.

The compounds can be used as antimycotics, inter alia, in the form of an aqueous emulsion, suspension or solution which can be administered per se. It is also possible to use aqueous solutions of the new salts of the said compounds (I).

THERAPEUTIC EFFECT 1 (1) in vitro-effect against human-phathogenic fungi:

The test medium was Milieu dpreuve according to Sabouraud.

The spectrum of activity and the intensity of activity (cglmpound i) (in vitro) can be seen from the following ta e:

Minimum inhibiting concentration as 7/m1.

Without serum Trich. aster-aides Trick. cruteriforme Trich. equimmi (N L) Tl-ich. equinum, Woolly (Hoeehst) Trich. equinum, gran. (Hoeehst)..

Trich. tonsura'ns (10) Trich. meaninii. (11) Trick. mentagrophuies-.... (12) Trich. rubrum (13) Microsp. audouim'i (14) Microsp. canis (NL) 1) Pen. comma... (22) Mucor mucedo (23) Blakeslea trispora. (24) Cami. alblcans I Fungistase.

(2) Elfect in vivo Equally effective results are produced when other compounds within the scope of (I) or salts of compound within the scope of (I) and specifically salts of compounds (a), (e), (f), (g), (i) and (P) are used. Compounds which are unsubstituted in the imidazole ring may be substituted in one phenyl group by a halogen atom, preferably chlorine or fluorine in the 0-, mor p-position; such compounds and their salts with hydrochloric acid, lactic acid or salicyclic acid are particularly useful. The following usages and dosage ranges are used for the compounds of the present invention:

(a) for use with humans:

( 1) dematomycoses, caused by fungi of the species Trychophytes, Microsporium, Epidermophytes, Aspergillus, Candida albicans and other yeasts;

(2) organomycoses caused by yeasts, mould fungi and dermatophytes;

(b) for veterinary use dermatomycoses and organomycoses caused by yeasts,

mould fungi and deramatophytes.

The compounds of the present invention are administered orally or parenterally as well as locally in the form of solutions, e.g., alcohol, preferably ethanol and isopropanol, buffer solutions, powders, tablets.

The dosage range for humans is in the range of from about 20 to about mg/kg. and preferably from about 40 to-about 60 mg./kg. Administration is generally recommended at intervals of about 12 hours and such administration should be continued for from about 10 to about 60 days.

Nevertheless it may sometimes be necessary to digress from the aforesaid amounts, dependent on the method of administration or also on account of individual reactions to the medicine or on the type of its formulation and the moment in time or the intervals at which it is adminis- 7 tered. In some cases, it may be sufiicient to use less than the minimum amount stated above, whereas in other cases it may be necessary to go beyond the stated upper limit. If larger amounts are applied, it may be advisable to distribute these over a day in several individual doses.

The compounds of the present invention can be used either as such or in combination with pharmaceutically acceptable carriers. Suitable forms for administration in combination with various inert carriers are tablets, capsules, powders, sprays, aqueous suspensions, injectable solutions, elixirs, syrups and the like. Carriers of this type comprise solid extenders or fillers, a sterile aqueous medium as well as various non-toxic organic solvents and the like. Obviously, the tablets and the like suitable for oral administration can be provided with an addition of saccharin or a similar additive. In the aforesaid case, the therapeutically active compound should be present in the total mixture at a concentration of about 0.5 to 90 percent by weight, i.e., in quantities which suflice to attain the range of dosage'mentioned above.

In the case of oral administration, obviously, tablets may also contain additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch and the like, and binders such as polyvinyl-pyrrolidone, gelatin and like. It is further possible to add lubricants such as magnesium stearate, sodium lauryl-sulphate and tale for producing tablets. In the case of aqueous suspension and/ or elixirs which are intended for oral administration, the active ingredient may be used together with various agents for improving the flavor, dyestuffs, emulsifiers and/or diluents, such as water, ethanol, propylene-glycol, glycerol and other compounds or combinations of this type.

In the case of parenteral administration, there may be used solutions of the active ingredients in sesame or peanut oil or in aqueous propylene-glycol of N,N-dimethylformamide, as well as sterile aqueous solutions the compounds are water-soluble. Such aqueous solution should be buffered in the usual manner, if required, and the liquid diluent should previously be rendered isotonic by the addition of the necessary amount of salt or glucose. These aqueous solutions are particularly suitable for intravenous, intramuscular and intraperitoneal injections.

In humans, a dosage of 40 mg./kg'. administered at intervals of 12 hours result in a blood level of between and 1 'y/ml. The half-life period in human serum in vivo amounts to 6 hours on the average. Up to to 40% of the administered amount of the substance are excreted with the urine in active form. The resorption quota amounts to more than 70% in the case of oral administration.

The LD for mice, rats, rabbits, dogs and cats lies between about 600 and 2200 mg. of the stated compou'nds/ kg. body weight in the case or oral administration.

The present invention also includes pharmaceutical compositions comprising at least one of the N-t'ritylimidazoles or salts thereof in admixture with a solid or liquid diluent or carrier which may be any of the conven- 8 tional diluents or carriers used in pharmaceutical sitions.

The present invention also includes unit dosage forms of medication which comprise at least one of the compounds of the present invention either alone or in admixture with a solid or liquid diluent or carrier. The compounds of the present application may include a protective envelope or cover containing the active compound within. Unit dosage form means that the composition is in the form of discrete portions, each containing a unit dose or a multiple or sub-multiple of the unit dose of the active ingredient which is the compound of the present invention. Such portions may, for example, be in monolithic coherent form, such as tablets, suppositories, pills or dragees; in wrapped or concealed form, such as wrapped powders, cachets, sachets or capsules, in ampules such as in sterile solution; or in other forms known to the art.

What is claimed is:

1. A method of treating fungal infections in humans and animals, which comprises administering to a human or animal so afilicted an amount suflicient to be therapeutically effective against said infection of a compound of the formula:

W N) Q-i-Q compoor a pharmaceutically acceptable non-toxic salt thereof.

2. A method according to claim 1, wherein the compound is 1-(trisphenyl-methyl)-imidazole.

3. A method according to claim 1, wherein the compound is N-triphenyl-methyl-imidazolium maleate.

4. A method according to claim 1, wherein the compound is N-triphenyl-methyl-imidazolium tartrate.'

5. A method according to claim 1, wherein the compoiiiid is N-triphenyl-methyl-imidazolium citrate.

6. A method according to claim 1, wherein the compound is N-triphenyl-methyl-imidazolium acetate.

7. A method according to claim 1, wherein the compound is N-triphenyl-methyl-imidazolium salicylate.

8. A jmethod according'to claim 1, wherein the compound is N-triphenyl-methyl-imidazolium sorbate.

9. A method according to claim 1, wherein the compound is N-triphenyl-methyl-imidazolium succinate.

.10. -A method according to claim 1, wherein the compound is N-triphenyl-methyl-imidazolium fumarate.

References Cited UNITED STATES PATENTS 3,321,366 5/1967 Mussell et a1. 424-273 JEROME D. GOLDBERG, Primary Examiner (5/59) CERTIFICATE OF CORREC'HN' P atent: No. 3,660,576 Dated May 2-, 1972 Inventor) KARL-HEINZ BUCHEL and MANFRED P'LEMPEL It is certified that: error appears in the above-eidentified parent and that said Letters Patent are hereby corrected as shown below:

r. At Column 2, Formula (I) should-be:

Signed and sealed this 22nd day of August 1972.

(SEAL) Attest:

ROBERT GOTTSCHALK Commissioner of Patents EDWARD M.FLETCHER,JR. Attesting Officer 

